Mental Health and Behavioral Disorders in Pregnancy

Diagnosis and Prevalence During Pregnancy and Postpartum

In the DSM-5, an episode of major depressive disorder (MDD) is defined as at least a 2-week period of either persistently depressed mood or loss of interest or pleasure in daily activities (required “gatekeeper” symptoms) plus four associated symptoms (or three if both gatekeeper symptoms are present) ( Box 59.1 ). Persistent means the symptom must be present for most of the day nearly every day. The patient must also have impairment of function in interpersonal relationships or work. It is possible to have a diagnosis of MDD without the symptom of depression. A woman could have persistent loss of interest or pleasure (but no sadness) and four of the other symptoms noted in Box 59.1 . Appetite, sleep, and motor activity can be either decreased or increased relative to the woman's norm. A fatigued woman who derives no pleasure from previously enjoyable activities, sleeps 15 hours a day, sits immobile for long periods, and gains weight has MDD. A guilt-ridden woman with sadness, 4 hours of sleep nightly, weight loss of 15 pounds, and pacing also has an MDD, which may be episodic or chronic.

Nearly twice as many women (12.0%) as men (6.6%) suffer from MDD each year. Women are at the greatest risk for MDD between 25 and 44 years of age, the primary age range for childbearing. The period prevalence of MDD is 12.7% during pregnancy (with 7.5% of women having a new episode), and 21.9% the year after parturition ; therefore MDD is among the most common complications of childbearing. Mothers at increased risk for depression are socioeconomically disadvantaged, have preterm infants, and are adolescents. Depression persists from months to years after childbirth, with lingering limitations in physical and psychologic functioning after recovery. Twenty-five to 50% of women with postpartum MDD have episodes lasting 7 months or more.

A woman's history of depression is the most important factor for assessing her risk for MDD during pregnancy. A previous episode lasting longer than 5 years nearly triples the risk for MDD in pregnancy (HR, 2.7; 95% CI, 1.5 to 4.7), whereas four or more episodes increase the risk by 3.6-fold (95% CI, 1.9 to 7.0). Stressful life events are predictors of a postpartum onset of MDD. Women with postpartum MDD have about a 25% to 33% risk for recurrence after a subsequent birth, and over 40% have MDD outside of pregnancy or the postpartum period. Depression is often a chronic, recurrent disorder.

The DSM-5 allows the designation with peripartum onset to specify episodes that begin during pregnancy or within the first 4 weeks postpartum. Epidemiologists have defined the duration of postpartum based on data about the break point between elevated risk for psychiatric illness after birth and the baseline risk for episodes in women of childbearing age. A significant peak in the rate of onset of mood disorders occurs in the 90-day period following childbirth. Although the definition of postpartum varies, the adverse effects of the disorder for the woman and her family are independent of time of onset.

The most commonly used measure to screen for MDD during childbearing is the Edinburgh Postnatal Depression Scale (EPDS, Fig. 59.2 ), which has been validated both during and after pregnancy. This self-report measure contains 10 items ranked from 0 to 3. It is scored by simple addition, and healthcare professionals can avail it for free. It is available in more than 23 languages. A cutoff score of greater than or equal to 13 (sensitivity, 86%; specificity, 78%; positive predictive value, 73%) for MDD has been recommended for screening in clinical settings. For pregnant women the recommended cutoff score is greater than or equal to 15. As with any screening tool, a positive test must be followed by diagnostic evaluation and treatment guidance. The differential diagnosis of MDD in the early postpartum period includes the “baby blues,” a transient syndrome occurring in up to 80% of mothers, which resolves within 2 weeks postpartum.

Natural History Across Childbearing

Periods of hormonal fluctuation (menstrual cycle, pregnancy, postpartum, and perimenopause) are associated with a higher risk for the emergence of MDD. The rapid change in gonadal steroid concentrations contributes to the etiology of postpartum onset MDD. The neurobiology of women who develop postpartum depression appears especially vulnerable to the mood-destabilizing effects of rapidly dropping concentrations of gonadal steroids.

Postpartum MDD does not differ from MDD at other periods during the childbearing years with respect to clinical presentation and duration of untreated episodes. However, aggressive obsessional thoughts occur more commonly in women who have postpartum-onset MDD compared with those suffering from depression outside the 1-year postpartum period. These more common obsessional thoughts that occur in the context of depression must be differentiated from delusions. Obsessions are recurrent, and persistent thoughts, impulses, or images are experienced as intrusive and inappropriate and cause marked anxiety or distress. For example, some mothers have obsessional thoughts about drowning their baby and refuse to bathe the child. Women often have frightening “what if” questions such as: “What if I put the baby in the microwave?” Obsessions differ from psychotic symptoms because patients recognize that the thoughts, impulses, or images are products of their own minds (not imposed by an external force, as in psychosis). Additionally, obsessional visual images may occur but are brief and perceived as being in the “mind's eye,” as opposed to an external hallucination. For example, a woman might have frightening images of her dead baby lying in a bathtub, but she would be aware that the image was not actually present in the real world. This distinction is important clinically because women with obsessional thoughts are vigilant about preventing any action related to the thought content. For example, if a mother has obsessional thoughts about stabbing her infant, she may insist that all knives be locked away. In contrast, women with psychosis may act on their thoughts. Although these symptom sets are not mutually exclusive, co-occurrence is very rare.

Perinatal depression affects reproductive outcomes. The physiologic dysregulations and psychosocial sequelae of MDD negatively affect pregnancy outcomes independent of antidepressant exposure. MDD is associated with poor prenatal care compliance, inadequate nutrition, obesity, smoking, alcohol and drug use, violence, poverty, and suicide. Perinatal mood disorders are associated with increased risks for maternal and infant mortality and morbidity. The Council on Patient Safety in Women's Health Care has published an evidence-based patient safety bundle that incorporates screening, intervention, referral, and follow-up into maternity care practice.

In a meta-analysis, Grote and colleagues reported that maternal MDD or depressive symptoms during pregnancy increase the risk of adverse pregnancy outcomes. The associations between antenatal depression and adverse outcomes included preterm birth (PTB) (RR, 1.13; 95% CI, 1.06 to 1.21) and low birthweight (LBW) (RR, 1.18; 95% CI, 1.07 to 1.30). The magnitude of risk for PTB and LBW from MDD was comparable to the risk of smoking 10 or more cigarettes a day, but this is modest compared with the higher risks associated with black race and substance abuse. Depression and/or anxiety were associated with a threefold greater risk for preeclampsia, which may be related to the increased sympathetic activity characteristic of these psychiatric states. Children exposed to maternal MDD in utero have higher cortisol concentrations than infants of mothers who were not depressed, which constitutes a biochemical change that continues through adolescence and places the offspring at risk for developing mental illness. Children exposed to maternal MDD during fetal life are four times more likely than those not exposed to be depressed at age 16 years. Notably, maternal treatment of MDD during pregnancy normalizes infant cortisol concentrations.

Exposure to maternal depressive symptoms is associated with structural alterations in the fetal hippocampus, amygdala, and prefrontal cortex. Infants born to mothers with antenatal depressive symptoms have greater functional connectivity of the amygdala with the temporal cortex and insula as well as the left and right anterior cingulate, medial orbitofrontal, and ventromedial prefrontal cortices even after adjustment for maternal postpartum depression. This connectivity pattern is similar to those observed in adults with MDD. Offspring of pregnant women with MDD are also at risk for insecure attachment and sleep and eating disorders. Other childhood sequelae of maternal mental illness are increased rates of accidental injury, child abuse, neglect, and infanticide. The relationship between maternal MDD and multiple childhood problems is a continuum that often begins during pregnancy.

Although MDD is a highly prevalent condition, only 1 in 5 Americans receive any guideline-concordant intervention, and the rate of intervention is lower in pregnant women than nonpregnant women . In nearly 6500 Medicaid recipients with established treatment for MDD, women who became pregnant had a significantly greater drop in both outpatient psychotherapy visits and antidepressant prescription claims than matched nonpregnant women, and care did not resume after birth.

The evidence-based treatments for MDD are psychotherapy and antidepressants. Studies of interpersonal psychotherapy and pharmacotherapy document both reduced depressive symptoms and improved maternal function following treatment during pregnancy. Psychotherapy is the preferred treatment for most women; however, it is not available in all practice settings, nor is it feasible for resource-challenged mothers. Barriers to clinic-based depression care include the physical demands of pregnancy, transportation, childcare, and cost. Adult outpatient settings do not typically offer flexible appointment schedules and many do not welcome children. If psychotherapy is not feasible or the woman prefers pharmacotherapy, decision making tends to focus on the potential adverse effects of medication rather than the adverse effects of MDD. The result is often a choice by the woman or her physician to avoid or stop drug treatment to obviate fetal exposure to pharmacotherapy without equal consideration of the risks of MDD to both the mother and fetus. For many pregnant women, the reality is that accessible and acceptable mental health treatment is very limited.

Low treatment rates are a public health concern given accumulating evidence that MDD during pregnancy increases risk to the pregnant woman and fetus and affects long-term health outcomes for both. Federally funded home visitation programs for disadvantaged women are potential partners for integrated care with obstetricians and mental health professionals to improve rates of depression treatment. Collaborative care has also been demonstrated to improve access to mental health treatment with improved depression and anxiety symptoms in the perinatal setting. Collaborative care is a type of integrated care that adheres to five core principles: patient-centered team care, population-based care, measurement-based treatment to target, evidence-based care, and accountable care. A care manager serves as the hub, tracking symptom monitoring for all patients enrolled and ensuring implementation of specialist-provided stepped-care recommendations. Although randomized trials have demonstrated the efficacy of perinatal collaborative care, implementation studies demonstrating effectiveness are needed.

Treatment of Major Depressive Disorder During Pregnancy

A risk-benefit decision-making model for the treatment of MDD during pregnancy has been published. Individually tailored interventions are considered for their capacity to maximize maternal wellness while also minimizing adverse effects for the maternal-fetal pair. The patient and physician both contribute expertise to the process because the patient's assignment of her own values dictates her choice. For example, some women will not consent to pharmacotherapy during pregnancy regardless of the impairment related to the MDD. Others choose pharmacotherapy because they are not confident that other treatments will be efficacious or because discontinuing medication has invariably been followed by recurrence. The verbal informed consent process promotes the treatment alliance, recognizes the patient's responsibility to make choices for herself and her fetus, and provides an opportunity for ongoing assessment of her competence to make decisions.

Using the word safe is problematic, as it implies no possibility of an adverse effect to many patients. Confirming any exposure as harmless presents the impossible task of proving no adverse effect on any reproductive or developmental outcomes throughout the exposed offspring's lifespan. What can be estimated from available studies is the magnitude of a subset of reproductive risks in drug-treated women. The risk for multiple domains of reproductive toxicity considered in this chapter is as follows: miscarriage and stillbirth, birth defects, PTB, neonatal effects, and neurobehavioral development. A major methodologic challenge is confounding by indication , the difficulty separating the reproductive effects of the drug exposure from the sequelae, both physiologic and psychosocial, of the underlying MDD. Progress has been made in disentangling the effects of drug from those of the disease through the analysis of large datasets and sophisticated statistical applications, as described later in this chapter.

Members of the American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association (APA) developed a consensus document for antidepressant treatment during pregnancy. For mild cases of MDD in pregnant women, psychotherapy is the treatment of choice as the initial intervention. Several types of short-term (8 to 16 sessions) of manual-based psychotherapy are available, such as interpersonal psychotherapy and cognitive behavioral therapy (CBT). These treatments can be delivered by nonphysician professionals such as psychologists, psychiatric nurse clinicians, or licensed clinical social workers. The cost and accessibility of depression treatment also affects treatment selection.

For moderate to severe MDD with marked functional impairment, antidepressant pharmacotherapy or combination therapy (medication and psychotherapy) is appropriate. Established efficacy and tolerability of any antidepressant for the individual woman is a strong consideration in drug choice during the risk-benefit decision-making process. Women with chronic or highly recurrent MDD may be on maintenance antidepressant medication when pregnancy occurs. Such treatment is recommended after three or more episodes of MDD owing to the near-certain likelihood of recurrence. For pregnant women studied in an academic setting, the risk of relapse for those who discontinued antidepressant treatment proximate to conception was significantly greater than that among women who maintained treatment. Among 82 women who continued their medication, 21 (26%) relapsed, compared with 44 (68%) of 65 women who discontinued medication. In contrast, Yonkers et al. found that pregnant women who continued antidepressants experienced the same rate of MDD recurrence as those who stopped in a community sample of obstetric patients. However, the strongest predictor for recurrence in both studies was four or more episodes of MDD prior to pregnancy.

Selective Serotonin Reuptake Inhibitor Exposure and Reproductive Outcomes

MDD and its sequelae also affect the outcomes below and must be considered when the risks associated with exposure to a selective serotonin reuptake inhibitor (SSRI) are being assessed.

Integrative Treatments

Recognized as a treatment for seasonal (winter) MDD, light therapy has also been shown to be efficacious for nonseasonal MDD. Light therapy is delivered as an early-morning bolus of 10,000 lux illuminance with commercially available boxes for 30 minutes ( Fig. 59.3 ). The light units conform to stringent standards, with illumination of a broad visual field, lighting from above to avoid glare, and maximal ultraviolet screening. Light therapy for pregnant women with MDD was explored in a randomized controlled trial (RCT) with bright white (active) versus dim red (placebo) light delivered in the early morning for 1 hour across 5 weeks. The response rates were significantly greater for bright white than dim red light and comparable to data obtained from antidepressant drug treatment. MDD must be distinguished from depression in the context of bipolar disorder because morning light therapy may induce agitation or irritability indicative of hypomania or mixed mood states in women with bipolar disorder.

Poor nutrition contributes to the pathogenesis of MDD. Folate and vitamin B12 are needed for single-carbon metabolism involved in the synthesis of serotonin and other monoamine neurotransmitters and catecholamines. Folate, B12, iron, zinc, and selenium deficiencies are more common among depressed than nondepressed individuals. The depletion of nutrient reserves throughout pregnancy and lactation may increase a woman's risk for MDD. Marginal or low folate status also increases the likelihood of nonresponse to antidepressant medication as well as the probability of relapse.

Omega-3 fatty acids are essential long-chain polyunsaturated fatty acids found in nerve cell membranes. Eicosapentaenoic and docosahexaenoic acids are derived primarily from fish. The American diet is relatively deficient in omega-3 compared with omega-6 fatty acids and other fats. Increased requirements during pregnancy raise the risk of deficiency and potentially of MDD. Omega-3 fatty acids have been used to treat perinatal MDD in small RCTs, but efficacy beyond placebo has not been convincingly demonstrated. However, docosahexaenoic acid supplementation may attenuate the effects of maternal stress during late pregnancy and reduce fetal exposure to glucocorticoids in women living in urban low-income environments. Women who received supplementation reported less stress and had lower levels of stress hormones in the third trimester than placebo-treated women.

Treatment of Postpartum Major Depressive Disorder

Antidepressants effective for MDD in women outside of childbearing are similarly effective during the perinatal period. In a randomized comparative efficacy trial with no placebo, the tricyclic nortriptyline ( n = 54) was compared with sertraline ( n = 55), and the response rates were equal. The dosing started with 25 mg sertraline (for 2 days, then to 50 mg/d) and was increased every 2 weeks to a maximum of 150 and 200 mg/d, respectively. A major finding was that the dose of sertraline required for remission in this 8-week double-blind protocol was 100 mg/d or more, with many women requiring 150 to 200 mg/d. Therefore the usual starting dose of 50 mg/d was not efficacious for the majority of women and dose adjustment should be anticipated approximately 2 weeks after treatment initiation. Another RCT of sertraline compared with placebo demonstrated efficacy for sertraline with a mean dose of 100 ± 54 mg/d. Remission (PHQ-9 or EPDS score of 4 or less) is the goal of treatment.

In a small novel study of the efficacy of estradiol treatment, Gregoire et al. randomized women with severe postpartum MDD to placebo or estradiol delivered by transdermal patch (200 µg/d) for 6 months. By 3 months, 80% of the estradiol-treated and 31% of the placebo-treated group responded. Endometrial changes were found in three participants at the study conclusion (6 months) despite coadministration of dydrogesterone (10 mg/d, 12 days per month in the final 3 months of the RCT); however, these changes resolved at follow-up. The inclusion of women who took concurrent antidepressant medications limits the ability to discern an estradiol-specific effect. No further RCTs have been published. With respect to breastfeeding, no estradiol was detected in the milk of 18 women treated with transdermal estradiol 50 to 100 µg/d for 12 weeks.

Diagnosis and Prevalence

The diagnosis of MDD is limited to the lifetime experience of normal mood with episodes of depression; in contrast, bipolar disorder (BD) is characterized by normal, depressed, and euphoric or irritable mood states (mania or hypomania, its less intense form). Changes in energy and activity levels are prominent and parallel variations in mood. Mania is a persistent, abnormally euphoric, expansive or irritable mood state, with inflated self-esteem, agitation, heightened energy, racing thoughts, pressured speech, impulsive behaviors, distractibility, and poor judgment for a minimum of 1 week. Impairment in function must be present. Hypomania is defined by a minimum of 4 continuous days of persistently increased creativity, productivity, and sociability or increased irritability that family or coworkers notice. The woman's function may be enhanced by creativity and increased energy. Many artists, writers, and world leaders have this disorder. In women, irritability and depression rather than euphoria are the predominant mood states, and BD is frequently misdiagnosed as unipolar depression . Atypical symptoms of depression (increased appetite, weight gain, hypersomnia, low energy, and a sense of heaviness) typically appear in the fall or winter and resolve in spring. This subtype of depression is common in women with BD.

The lifetime prevalence of BD is 1% to 2%. BD type I, which affects women and men equally, is characterized by MDD and periods of mania or hypomania. The BD variants type II (MDD and hypomania only), mixed episodes (intermingled manic and depressive symptoms), and rapid cycling (four or more episodes of opposite polarity in 1 year) are more common in women than men. Women with BD often have comorbid anxiety disorders; alcohol or substance (especially marijuana) use disorders; bulimia nervosa; histories of childhood or adult physical and/or sexual abuse; and medical problems, including migraines, metabolic syndrome, pain disorders, and hypothyroidism.

The differentiation of MDD from BD is often challenging and delays of 7 to 11 years until the diagnosis are common. Prescribing an antidepressant without an antimanic drug for a woman with BD can precipitate agitation, irritability, mania, or mixed or rapid cycling episodes. In such cases the antidepressant must be discontinued. To screen patients for BD, the most commonly used measure is the Mood Disorders Questionnaire (MDQ) ( Fig. 59.4 ), which assesses lifetime history of mania with 13 yes/no symptoms and two additional questions: a yes/no query about whether symptoms occurred during the same time period and a designation of the degree to which the symptoms caused impairment in function. A positive screen requires seven or more symptoms during the same period that caused moderate or serious problems. The MDQ can be combined with the EPDS as a screening tool with modification of the original MDQ scoring for screening perinatal women. The traditional diagnostic interview established BD in 50% of women and in almost 70% when the MDQ was scored without the impairment criterion . The MDQ or a diagnostic assessment for BD should be given prior to prescribing antidepressants for a perinatal woman with symptoms of MDD.

Natural History Across Childbearing

The course of episodes is useful in evaluating the risk for recurrence of BD during pregnancy. Women with mood episodes occurring only after birth are not likely to relapse during pregnancy even without medication. However, women with a chronic course are likely to be symptomatic during pregnancy, and mood-stabilizing treatment is appropriate. For women with chronic BD, discontinuation of drug treatment proximal to conception incurred a high risk for recurrence (86%) compared with patients who continued treatment (37%). After birth, all women with BD are at high risk for recurrent mood episodes. Postpartum relapse rates of 66% (95% CI 57% to 75%) without medication treatment compared with 23% (95% CI, 14% to 37%) with prophylactic medication compel initiating treatment immediately postpartum to prevent relapse for women who have not been treated in pregnancy.

Postpartum psychosis is typically a manifestation of BD, such as depression, mixed state (both manic and depressive symptoms together), or mania with psychotic features. It occurs in 1 to 2 per 1000 births in the first month following delivery. Women are more vulnerable to psychosis in the postbirth period than at any other time during their lives. The massive reproductive hormone decline at delivery drives the risk for psychosis in vulnerable women. In the first 30 days after birth, a woman is 21.7 times more likely to develop psychosis than in the 2-year period prior to childbirth. After an index episode, 20% to 50% of women have only postpartum psychotic episodes without recurrence outside of childbearing. Sleep deprivation and circadian rhythm disturbance, autoimmune thyroiditis, and infections are treatable conditions that contribute to the risk for mood instability. Inborn errors of metabolism, particularly urea cycle disorders (characterized by high plasma ammonia concentrations) and autoimmune N-methyl-d-aspartate encephalitis are rare causes of psychosis after childbirth.

The clinical picture of postpartum psychosis is characterized by a rapid onset of severe mood fluctuations, marked cognitive impairment suggestive of delirium, bizarre behavior, insomnia, visual and auditory hallucinations, unusual hallucinations (tactile and olfactory), and impaired judgment and insight. Specific types of delusional thoughts are related to risk for infanticide. Delusional altruistic homicide (often associated with maternal suicide) to save both mother and baby “from a fate worse than death” was reported in a review of filicides. Sensitive direct questions about thoughts of harm to the infant are imperative in the examination. Nonjudgmental inquiry can be made as follows: “Some new mothers have thoughts such as wishing the baby were dead or about harming the baby; has this happened to you?”